1. Field of the Invention
The present invention relates to the oral delivery of parathyroid hormone (PTH). The mammalian parathyroid hormones, e.g. human (hPTH), bovine (bPTH) and porcine (pPTH), are single polypeptide chains of 84 amino acid residues having molecular weights of approximately 9500. Specifically, the present invention relates to PTH fragments incorporating at least the first 28 N-terminal amino acid residues (PTH (1-28)) up to and including the first 41 N-terminal amino acid residues (PTH (1-41)). More particularly, the invention is directed to pharmaceutical compositions for the oral delivery of PTH, said compositions comprising PTH (1-28) to (1-41) and N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC).
2. Description of the Related Art
PTH studies done in animals and humans with PTH, PTH-related peptides, and PTH analogues have demonstrated its usefulness in increasing bone formation and bone resorption and have prompted interest in its use for the treatment of osteoporosis and related bone disorders. However, the oral delivery of PTH in mammals has proven difficult due, at least in part, to the insufficient stability of PTH in the gastrointestinal tract as well as the inability of PTH to be readily transported through the intestinal walls into the blood stream.
U.S. Pat. No. 5,773,647 (the '647 patent) describes 193 carrier compounds useful for the delivery of active agents, including PTH. One of the carrier compounds expressly described therein is N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) having the formula
Example 2 in Column 6 of the '647 patent describes the preparation of 11 different dosing compositions some intracolonic (IC) and some oral gavage (PO) each containing parathyroid hormone and a carrier, the carrier being different for each composition. An IC dosing composition was prepared using 5-CNAC as the carrier. Example 3 therein describes in vivo tests carried out dosing male Sprague-Dawley rats with the dosing solutions prepared in Example 2. Blood samples were collected and the serum PTH concentration was quantified for each rat.
Surprisingly, it has now been found that 5-CNAC in combination with specific PTH fragments, i.e. PTH fragments incorporating at least the first 28 N-terminal amino acid residues (PTH (1-28)) up to and including the first 41 N-terminal amino acid residues (PTH (1-41)) when orally administered gives unexpectedly high PTH serum levels relative to other PTHs and other carriers and provide a sharp Cmax allowing for a bone formation effect.